Ingrid Hansen-Pupp

Validation of a New Retinopathy of Prematurity Screening Method Monitoring Longitudinal Postnatal Weight and Insulinlike Growth Factor I

OBJECTIVE To validate in a prospective study the surveillance algorithm WINROP for detecting infants at risk for proliferative retinopathy of prematurity (ROP). METHODS Fifty preterm infants with a mean gestational age of 26 weeks were included. In the first step of WINROP, weekly measures of body weight and serum insulinlike growth factor I (IGF-I) level from birth until postmenstrual age 36 weeks are entered and compared with expected development. If any of the variables show a negative deviation to a certain degree, an alarm is given. In the second step, gestational age, birth weight, and IGF binding protein 3 level are entered. RESULTS The WINROP algorithm identified all children (100% sensitivity) who were diagnosed with proliferative ROP 1.1 to 21.6 weeks later. No infants with no alarm or with alarm at low risk developed proliferative ROP. Alarm at high risk before postmenstrual age 32 weeks was given for 22 of 50 infants (44%); 9 of these infants developed proliferative ROP (54% specificity), of whom 8 were treated. CONCLUSION The WINROP algorithm may be a useful tool for modification of ROP screening.

New insights into the development of retinopathy of prematurity - importance of early weight gain

Evidence is accumulating that one of the strongest predictors of retinopathy of prematurity (ROP), in addition to low gestational age, is poor weight gain during the first weeks of life. In infants born preterm, the retina is not fully vascularised. The more premature the child, the larger is the avascular area. In response to hypoxia, vascular endothelial growth factor (VEGF) is secreted. For appropriate VEGF‐induced vessel growth, sufficient levels of insulin‐like growth factor I (IGF‐I) in serum are necessary. IGF‐I is a peptide, related to nutrition supply, which is essential for both pre‐ and post‐natal general growth as well as for growth of the retinal vasculature. In prematurely born infants, serum levels are closely related to gestational age and are lower in more prematurely born infants. At preterm birth the placental supply of nutrients is lost, growth factors are suddenly reduced and general as well as vascular growth slows down or ceases. In addition, the relative hyperoxia of the extra‐uterine milieu, together with supplemental oxygen, causes a regression of already developed retinal vessels. Postnatal growth retardation is a major problem in very preterm infants. Both poor early weight gain and low serum levels of IGF‐I during the first weeks/months of life have been found to be correlated with severity of ROP.

Circulating interferon-gamma and white matter brain damage in preterm infants

The fetal inflammatory response has been suggested as causal in neonatal morbidity. Serial levels of circulating cytokines were evaluated in 74 infants with a mean gestational age (GA) of 27.1 wk. Pro-inflammatory and modulatory (IL-4, IL-10) cytokines were analyzed from cord blood, and at 6, 24, and 72 h postnatal age. Measure of cytokine burden over time was assessed by calculating the area under curve (AUC) for analyzed levels (0–72 h). Premature rupture of membranes (PROM) was associated with higher levels of IL-2 at birth and at 6 h, of IFN-γ at 6 and 24 h postnatal age and of TNF-α at 6 and 24 h. Levels of IFN-γ at 6, 24, and 72 h were increased in infants developing white matter brain damage (WMD) compared with those without WMD. Infants with arterial hypotension requiring dopamine treatment had an increase in IL-6 with a peak at 6 h of age. Severe intraventricular hemorrhage (IVH) was associated with increase in AUC, whereas WMD was associated with increase in AUC. A fetal immune response with increased postnatal levels of IFN-γ was associated with development of WMD. PROM was associated with a T-helper 1 cytokine response with increased levels of IFN-γ. Type of inflammatory response appears of importance for subsequent morbidity.

Influence of Insulin-Like Growth Factor-I and Nutrition during Phases of Postnatal Growth in Very Preterm Infants.

Pronounced growth restriction (GR) occurs after very preterm birth. The interaction between IGF-I, nutritional intake, and growth was evaluated prospectively in 64 infants with a mean (SD) GA of 25.7 (1.9) wk. Blood sampling of IGF-I and measurements of weight, length, and head circumference were performed weekly until discharge. Daily calculation of nutritional intake was performed. Standard deviation scores (SDSs) for growth parameters defined two growth phases: GR phase (birth until lowest SDS) and catch-up (CU) phase (lowest SDS until 35 gestational weeks). IGF-I concentrations during the first postnatal weeks were low and increased at 30 wk GA, irrespective of GA at birth, coinciding with initiation of CU growth. Concentrations of IGF-I were positively associated with change in weight SDS during the GR phase, p = 0.001 and CU phase, p = 0.004–0.027. Protein and energy intake were not associated with change in SDS weight during the GR phase as opposed to the CU phase (p < 0.001, respectively). Nutritional intake did not correlate to concentrations of IGF-I before 30 wk GA. IGF-I is associated with growth at an earlier postnatal age than nutrient intake and the effect of nutrition on levels of IGF-I may be restricted to the period of established CU growth.

Early amplitude-integrated EEG correlates with cord TNF-alpha and brain injury in very preterm infants

Aim: To investigate if the early electroencephalogram (EEG) and amplitude‐integrated EEG (aEEG) in very preterm infants is affected by perinatal inflammation and brain injury, and correlates with long‐term outcome.

Postnatal Decrease in Circulating Insulin-Like Growth Factor-I and Low Brain Volumes in Very Preterm Infants

CONTEXT IGF-I and IGF binding protein-3 (IGFBP-3) are essential for growth and maturation of the developing brain. OBJECTIVE The aim of this study was to evaluate the association between postnatal serum concentrations of IGF-I and IGFBP-3 and brain volumes at term in very preterm infants. DESIGN Fifty-one infants with a mean (sd) gestational age (GA) of 26.4 (1.9) wk and birth weight (BW) of 888 (288) g were studied, with weekly blood sampling of IGF-I and IGFBP-3 from birth until 35 gestational weeks (GW) and daily calculation of protein and caloric intake. Magnetic resonance images obtained at 40 GW were segmented into total brain, cerebellar, cerebrospinal fluid, gray matter, and unmyelinated white matter volumes. MAIN OUTCOME MEASURES We evaluated brain growth by measuring brain volumes using magnetic resonance imaging. RESULTS Mean IGF-I concentrations from birth to 35 GW correlated with total brain volume, unmyelinated white matter volume, gray matter volume, and cerebellar volume [r = 0.55 (P < 0.001); r = 0.55 (P < 0.001); r = 0.44 (P = 0.002); and r = 0.58 (P < 0.001), respectively]. Similar correlations were observed for IGFBP-3 concentrations. Correlations remained after adjustment for GA, mean protein and caloric intakes, gender, severe brain damage, and steroid treatment. Protein and caloric intakes were not related to brain volumes. Infants with BW small for GA had lower mean concentrations of IGF-I (P = 0.006) and smaller brain volumes (P = 0.001-0.013) than infants with BW appropriate for GA. CONCLUSION Postnatal IGF-I and IGFBP-3 concentrations are positively associated with brain volumes at 40 GW in very preterm infants. Normalization of the IGF-I axis, directly or indirectly, may support normal brain development in very preterm infants.

Inflammation at birth and the insulin-like growth factor system in very preterm infants.

Background: Foetal inflammation is associated with an increased risk of brain damage in preterm infants whereas IGF‐I is essential for cerebral development and exhibits anti‐apoptotic properties.

Insulin-like growth factor 1 has multisystem effects on foetal and preterm infant development

Poor postnatal growth after preterm birth does not match the normal rapid growth in utero and is associated with preterm morbidities. Insulin‐like growth factor 1 (IGF‐1) axis is the major hormonal mediator of growth in utero, and levels of IGF‐1 are often very low after preterm birth. We reviewed the role of IGF‐1 in foetal development and the corresponding preterm perinatal period to highlight the potential clinical importance of IGF‐1 deficiency in preterm morbidities.

Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants

Background:To evaluate the relationships between postnatal change in circulatory insulin-like growth factor-I (IGF-I) concentrations, brain volumes, and developmental outcome at 2 y of age in very preterm infants.Methods:IGF-I was measured weekly, and nutritional intake was calculated daily from birth until a postmenstrual age (PMA) of 35 wk. Individual β coefficients for IGF-I, IGF-I(B), representing the rate of increase in IGF-I from birth until a PMA of 35 wk were calculated. Brain magnetic resonance imaging was performed at term age, with segmentation into total brain, cerebellar, gray matter, and unmyelinated white matter volume (UWMV). Developmental outcome was evaluated using Bayley Scales of Infant Development-II.Results:Forty-nine infants, with mean gestational age (GA) of 26.0 wk, were evaluated at mean 24.6 mo corrected age. Higher IGF-I(B), UWMV, and cerebellar volume were associated with a decreased risk for a Mental Developmental Index (MDI) < 85 (odds ratio (95% confidence interval): 0.6 (0.4–0.9), 0.96 (0.94–0.99), and 0.78 (0.6–0.96), respectively). In multivariate analysis, higher IGF-I(B) and higher UWMV combined with female gender constituted the two models with the highest predictive value for MDI > 85.Conclusion:A higher rate of increase in circulating IGF-I is associated with a decreased risk for subnormal MDI at 2 y of corrected age. This relationship is in part dependent on brain volume at term age.

Longitudinal infusion of a complex of insulin-like growth factor-I and IGF-binding protein-3 in five preterm infants: pharmacokinetics and short-term safety

Background:In preterm infants, low levels of insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) are associated with impaired brain growth and retinopathy of prematurity (ROP). Treatment with IGF-I/IGFBP-3 may be beneficial for brain development and may decrease the prevalence of ROP.Methods:In a phase II pharmacokinetics and safety study, five infants (three girls) with a median (range) gestational age (GA) of 26 wk + 6 d (26 wk + 0 d to 27 wk + 2 d) and birth weight of 990 (900–1,212) g received continuous intravenous infusion of recombinant human (rh)IGF-I/rhIGFBP-3. Treatment was initiated during the first postnatal day and continued for a median (range) duration of 168 (47–168) h in dosages between 21 and 111 µg/kg/24 h.Results:Treatment with rhIGF-I/rhIGFBP-3 was associated with higher serum IGF-I and IGFBP-3 concentrations (P < 0.001) than model-predicted endogenous levels. Of 74 IGF-I samples measured during study drug infusion, 37 (50%) were within the target range, 4 (5%) were above, and 33 (45%) were below. The predicted dose of rhIGF-I/rhIGFBP-3 required to establish circulating levels of IGF-I within the intrauterine range in a 1,000 g infant was 75–100 µg/kg/24 h. No hypoglycemia or other adverse effects were recorded.Conclusion:In this study, continuous intravenous infusion of rhIGF-I/rhIGFBP-3 was effective in increasing serum concentrations of IGF-I and IGFBP-3, and was found to be safe.